tbuckley/cabot-search huggingface dataset:
Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study
Authors: Samantha Gadd, Vicki Huff, Andrew D. Skol, Lindsay A. Renfro, Conrad V. Fernandez, Elizabeth A. Mullen, Corbin D. Jones, Katherine A. Hoadley, Kai Lee Yap, Nilsa C. Ramirez, Sheena Aris, Quy H. Phung, Elizabeth J. Perlman
Journal: Cell Reports Medicine (2022)

Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response.
Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial
Authors: Kanwal P Raghav, Bettzy Stephen, Daniel D Karp, Sarina A Piha-Paul, David S Hong, Dipti Jain, Dilichukwu O Chudy Onwugaje, Abdulrahman Abonofal, Anneleis F Willett, Michael Overman, Brandon Smaglo, Ryan W Huey, Funda Meric-Bernstam, Gauri R Varadhachary, Aung Naing
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Cancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the efficacy of pembrolizumab, a programmed cell death-1 inhibitor, in patients with CUP. Methods The study was designed as a phase 2 basket trial for independent rare tumor cohorts including CUP. Adult patients with CUP who had progressed on previous systemic therapy, performance status 0/1 and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST V.1.1) were eligible. Patients received pembrolizumab (200 mg) intravenously every 21 days. Twenty-nine patients were enrolled and treated between August 2016 and June 2020. The primary endpoint was non-progression rate (NPR) at 27 weeks (NPR-27) per immune-related RECIST. Key prespecified secondary endpoints were confirmed objective response rate (ORR), safety, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Pretreatment biopsies were examined for biomarkers of response (programmed cell death ligand-1 (PD-L1) expression and tumor infiltrating lymphocytes (TILs)). Results Among 25 (of 29 enrolled) eligible and evaluable patients, 14 (56%) had poorly differentiated carcinoma. Patients received a median of two lines of therapy prior to enrollment. Median follow-up was 27.3 months. NPR-27 was observed in seven patients (28.0% (95% CI: 12.1 to 49.4)). ORR was 20.0% (95% CI: 6.8 to 40.7) with five patients achieving immune-related partial response with median DoR of 14.7 months (95% CI: 9.8 to 19.6). Median PFS and OS were 4.1 (95% CI: 3.1 to 5.1) and 11.3 (95% CI: 5.5 to 17.1) months, respectively. Treatment-related adverse events of any and grade ≥3 were seen in 19 (76%) and 4 (16%) patients, respectively. One (4%) patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Neither PD-L1 nor TILs were associated with NPR-27. Both positive PD-L1 staining (44.4% vs 6.3%; p=0.040) and intense TIL infiltration (44.4% vs 6.3%; p=0.040) were associated with response. Conclusion Pembrolizumab showed encouraging efficacy in patients with CUP with acceptable safety profile. Trial registration number NCT02721732 .
PIK3CA mutations-mediated downregulation of circLHFPL2 inhibits colorectal cancer progression via upregulating PTEN
Authors: Xiaodan Chong, Jingde Chen, Nanxin Zheng, Zhuqing Zhou, Yanan Hai, Shiqing Chen, Yu Zhang, Qingzhuo Yu, Shijun Yu, Zhiqin Chen, Wenfang Bao, Ming Quan, Zhe-Sheng Chen, Yangyang Zhan, Yong Gao
Journal: Molecular Cancer (2022)

Abstract Background PIK3CA mutation and PTEN suppression lead to tumorigenesis and drug resistance in colorectal cancer (CRC). There is no research on the role of circular RNAs (circRNAs) in regulating PIK3CA mutation and MEK inhibitor resistance in CRC. Methods The expression of circLHFPL2 in PIK3CA-mutant and wild-type cells and tissues was quantified by RNA-sequencing and qRT-PCR. CCK-8 assay and colony formation assay were used to evaluate cell viability. Annexin V/PI staining was implemented to assess cell apoptosis. Luciferase assay, biotin-coupled microRNA capture, and RIP assay were used to validate the interaction among potential targets. Western blotting and qRT-PCR assays were used to evaluate the expression of involved targets. Xenograft tumor in a nude mouse model was used to explore the role of circRNAs in vivo. Results RNA sequencing defined downregulated expression of circLHFPL2 in both PIK3CA H1047R (HCT116) and PIK3CA E545K (DLD1) cells. CircLHFPL2 was also downregulated in PIK3CA-mutant CRC primary cells and tissues, which was correlated with poor prognosis. CircLHFPL2 was mainly localized in the cytoplasm and its downregulation was attributed to the PI3K/AKT signaling pathway activated by phosphorylating Foxo3a. CircLHFPL2 inhibited PI3KCA-Mut CRC progression both in vitro and in vivo. Furthermore, our work indicated that circLHFPL2 acts as a ceRNA to sponge miR-556-5p and miR-1322 in CRC cells and in turn modulate the expression of PTEN. Importantly, circLHFPL2 was able to overcome PIK3CA-mediated MEK inhibitor resistance in CRC cells. Conclusions Downregulation of circLHFPL2 sustains the activation of the PI3K/AKT signaling pathway via a positive feedback loop in PIK3CA-mutant CRC. In addition, downregulation of circLHFPL2 leads to MEK inhibitor resistance in CRC. Therefore, targeting circLHFPL2 could be an effective approach for the treatment of CRC patients harboring oncogenic PIK3CA mutations.
Does Intrapartum Epidural Analgesia Increase the Risk of Autism Spectrum Disorder in Offspring? Most Likely Not
Authors: Angela Lupattelli, Hedvig Nordeng
Journal: JAMA Network Open (2022)

There is no doubt that epidural analgesia is one of the most effective methods of pain relief in labor,1 with up to 7 of every 10 women receiving such analgesia during delivery.2 Local anesthetic with or without adjunct opioid is therefore one of the most common prenatal drug exposures.
Tumor-associated Tregs obstruct antitumor immunity by promoting T cell dysfunction and restricting clonal diversity in tumor-infiltrating CD8+ T cells
Authors: David Noyes, Arup Bag, Saheed Oseni, Jon Semidey-Hurtado, Ling Cen, Amod A Sarnaik, Vernon K Sondak, Dennis Adeegbe
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Accumulation of regulatory T cells (Treg) has been described to often correlate with poor prognosis in many solid tumors. How Treg presence impinges on limited functionality and clonal composition of tumor-associated CD8 +T cells has important implications for their therapeutic targeting in the tumor microenvironment. In the present study, we investigated how accumulation of Tregs contributes to T cell dysfunction and clonal constriction of tumor-infiltrating CD8 +T cells. Methods Resected melanoma and lung adenocarcinoma tissues from tumor-bearing mice or patients were analyzed. The proportions and phenotype as well as clonal diversity of tumor-associated CD8 +T cells were evaluated by flow cytometry and single-cell T-cell receptor (TCR) sequencing, respectively, at early or advanced tumor stages or under Treg depletion conditions. Furthermore, antigen-specific T cells were evaluated on adoptive transfer into tumor-bearing mice in the presence or absence of anti-CTLA-4 antibody or CTLA-4 Ig. Lastly, tumor-bearing mice were treated with anti-KLRG1 antibody and/or bromodomain inhibitor JQ1 with interleukin (IL)-2 immune complexes to determine therapeutic efficacy. Results We demonstrate that the emergence of exhaustion-like phenotype and impaired effector functionality in tumor-associated CD8 +T cells is positively correlated with Treg accumulation in the tumor bed and this dysfunctional phenotype becomes reversed on Treg reduction in murine melanoma and lung cancer models. Heightened tumor-associated Treg-expressed CTLA-4 is key to emergence and sustenance of this phenotype. Furthermore, TCR sequencing revealed a clonal shrinkage of tumor-infiltrating CD8 +T cells as tumor progressed, which was associated with reduced survival profile concomitant to increasing Treg proportions. Limited IL-2 availability was a key mechanism contributing to this peripheral repertoire reshaping as Treg depletion improved IL-2 levels, rescued CD8 +T cell viability, and improved their clonal diversity. Finally, targeted reduction of tumor but not peripheral Tregs through JQ1 and/or anti-KLRG1 antibody significantly improved antitumor response in melanoma-bearing mice when supplemented with IL-2 immune complexes. Conclusion Collectively, our study reveals a bimodal program enacted by Tregs to support T cell dysfunction in the tumor bed and highlights a promising therapeutic regimen for localized reprogramming of the tumor microenvironment to curb Treg impairment of antitumor CD8 +T cell response in favor of improved antitumor immunity.
RCT Evidence Supports Incorporating Nonoperative Management Option for Uncomplicated Acute Appendicitis—How to Implement This in Clinical Practice?
Authors: Paulina Salminen
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Flowers for Other Lives
Authors: David Haosen Xiang
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Agreement and Correlation Between Different Topical Corticosteroid Potency Classification Systems
Authors: Alexa C. Bowie, Mina Tadrous, Alexander Egeberg, Jane Harvey, Stephanie J. Lax, Jacob P. Thyssen, Aaron M. Drucker
Journal: JAMA Dermatology (2022)

<h3>Importance</h3> Topical corticosteroids (TCSs) are available in multiple potencies that alter their effectiveness and safety. Pharmacoepidemiologic studies on TCSs are hampered by the absence of a universal potency classification system, limiting comparisons across studies, robust exposure classification, and clinical interpretation. <h3>Objective</h3> To classify TCSs into 3 commonly used potency classification systems and evaluate the agreement and correlation between the 3 systems. <h3>Design, Setting, and Participants</h3> In this classification study, a comprehensive list of TCS formulations was compiled using sources identified in the literature, the Ontario Drug Benefit Formulary, a recent Cochrane review on the use of TCSs in people with eczema, and the Anatomical Therapeutic Classification (ATC) of the World Health Organization from August 11, 2021, to January 6, 2022. Topical corticosteroid potency classifications were assigned and compared using the 7-category US classification system, a 4-category classification from a recent Cochrane review largely based on the UK formulary, and the 4-category ATC classification. To facilitate comparisons across systems, the 7-category US system was consolidated into 4 categories. <h3>Main Outcomes and Measures</h3> Cohen weighted κ (κ<sub>w</sub>) and Spearman rank correlation coefficients (<i>r</i>) were computed to examine agreement and correlation between the classification systems. <h3>Results</h3> A total of 232 unique TCS formulations (ATC, n = 231; US classification, n = 232; Cochrane review, n = 89) were included. Overall, there was low-to-moderate agreement but strong correlation between the classification systems. The US classification had weak agreement with the ATC system (κ<sub>w</sub>, 0.53; 95% CI, 0.45-0.60) and moderate agreement with the Cochrane review classification (κ<sub>w</sub>, 0.60; 95% CI, 0.48-0.73); there was weak agreement between the ATC and Cochrane review classifications (κ<sub>w</sub>, 0.58; 95% CI, 0.46-0.71). The US classification strongly correlated with the ATC system (<i>r</i>, 0.77; 95% CI, 0.71-0.82) and Cochrane review classification (<i>r</i>, 0.74; 95% CI, 0.62-0.82). There was also a strong correlation between the Cochrane review and ATC classifications (<i>r</i>, 0.71; 95% CI, 0.58-0.80). <h3>Conclusions and Relevance</h3> This classification study used multiple resources to classify 232 TCS formulations into 3 potency classifications. Because these systems are often incongruent, they may yield different results in pharmacoepidemiologic studies; investigators need to be transparent in their classification approach and consider alternative potency definitions in sensitivity analyses.
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Journal: JAMA Network Open (2022)

Ignacio Illán-Gala, MD, PhD; Salvatore Nigro, PhD, PhD; Lawren VandeVrede, MD, PhD; Neus Falgàs, MD, PhD; Hilary W. Heuer, PhD; Cèlia Painous, MD; Yaroslau Compta, MD, PhD; Maria J. Martí, MD, PhD; Victor Montal, MSc, PhD; Javier Pagonabarraga, MD, PhD; Jaime Kulisevsky, MD, PhD; Alberto Lleó, MD, PhD; Juan Fortea, MD, PhD; Giancarlo Logroscino, MD, PhD; Andrea Quattrone, MD; Aldo Quattrone, MD; David C. Perry, MD; Maria Luisa Gorno-Tempini, MD, PhD; Howard J. Rosen, MD; Lea T. Grinberg, MD, PhD; Salvatore Spina, MD, PhD; Renaud La Joie, PhD; Gil D. Rabinovici, MD; Bruce L. Miller, MD; Julio C. Rojas, MD; William W. Seeley, MD; Adam L. Boxer, MD, PhD
A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia
Authors: Andy G. X. Zeng, Suraj Bansal, Liqing Jin, Amanda Mitchell, Weihsu Claire Chen, Hussein A. Abbas, Michelle Chan-Seng-Yue, Veronique Voisin, Peter van Galen, Anne Tierens, Meyling Cheok, Claude Preudhomme, Hervé Dombret, Naval Daver, P. Andrew Futreal, Mark D. Minden, James A. Kennedy, Jean C. Y. Wang, John E. Dick
Journal: Nature Medicine (2022)
Case 16-2022: A 55-Year-Old Man with Fevers, Night Sweats, and a Mediastinal Mass
Authors: David C. Fajgenbaum, Reece J. Goiffon, Jacob D. Soumerai, Cynthia K. Harris
Journal: New England Journal of Medicine (2022)

A 55-year-old man was evaluated for a mediastinal mass, which was identified during an evaluation for waxing and waning fevers, night sweats, and fatigue. He had mediastinal lymphadenopathy with low FDG uptake, splenomegaly, anasarca, elevated inflammatory marker levels, hypoalbuminemia, anemia, and thrombocytopenia. A diagnosis was made.
Bufalin stimulates antitumor immune response by driving tumor-infiltrating macrophage toward M1 phenotype in hepatocellular carcinoma
Authors: Zhuo Yu, Yuyao Li, Yue Li, Jinghao Zhang, Man Li, Longshan Ji, Yifei Tang, Yanxi Zheng, Jianguo Sheng, Qiucheng Han, Fu Li, Jianfeng Guo, Lingtai Wang, Xuehua Sun, Yueqiu Gao, Hai Feng
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Immunotherapy for hepatocellular carcinoma (HCC) exhibits limited clinical efficacy due to immunosuppressive tumor microenvironment (TME). Tumor-infiltrating macrophages (TIMs) account for the major component in the TME, and the dominance of M2 phenotype over M1 phenotype in the TIMs plays the pivotal role in sustaining the immunosuppressive character. We thus investigate the effect of bufalin on promoting TIMs polarization toward M1 phenotype to improve HCC immunotherapy. Methods The impact of bufalin on evoking antitumor immune response was evaluated in the immunocompetent mouse HCC model. The expression profiling of macrophage-associated genes, surface markers and cytokines on bufalin treatment in vitro and in vivo were detected using flow cytometry, immunofluorescence, western blot analysis, ELISA and RT-qPCR. Cell signaling involved in M1 macrophage polarization was identified via the analysis of gene sequencing, and bufalin-governed target was explored by immunoprecipitation, western blot analysis and gain-and-loss of antitumor immune response. The combination of bufalin and antiprogrammed cell death protein 1 (anti-PD-1) antibody was also assessed in orthotopic HCC mouse model. Results In this study, we showed that bufalin can function as an antitumor immune modulator that governs the polarization of TIMs from tumor-promoting M2 toward tumor-inhibitory M1, which induces HCC suppression through the activation of effector T cell immune response. Mechanistically, bufalin inhibits overexpression of p50 nuclear factor kappa B (NF-κB) factor, leading to the predominance of p65-p50 heterodimers over p50 homodimers in the nuclei. The accumulation of p65-p50 heterodimers activates NF-κB signaling, which is responsible for the production of immunostimulatory cytokines, thus resulting in the activation of antitumor T cell immune response. Moreover, bufalin enhances the antitumor activity of anti-PD-1 antibody, and the combination exerts synergistic effect on HCC suppression. Conclusions These data expound a novel antitumor mechanism of bufalin, and facilitate exploitation of a new potential macrophage-based HCC immunotherapeutic modality.
Gastrojejunostomy in a patient with previous choledochoduodenostomy and duodenal stent with transcholedocical approach
Authors: Benedetto Mangiavillano, Francesco Auriemma, Danilo Paduano, Laura Lamonaca, Alessandro Repici
Journal: Endoscopy (2022)

A 70-year-old woman was admitted to our emergency room due to vomiting for 2 days. The patient had a previous diagnosis of bladder neoplasia with pancreatic head metastasis, and 15 days prior to admission she had undergone placement of a duodenal self-expandable metal stent (SEMS) plus endoscopic ultrasound (EUS)-guided choledochoduodenostomy (CDS) because of jaundice and vomiting due to the compression of the proximal descending duodenum and common bile duct (CBD). A computed tomography scan showed gastric outlet obstruction due to SEMS migration into the third duodenal portion, with the proximal end of the SEMS hitting against the duodenal wall. Because of this complex case we decide to perform an EUS-guided gastrojejunostomy (EUS-GJ) aided by nasobiliary drain (NBD) to target the jejunal loop and avoid puncture of an ileal or colonic loop.
Risk of Hematologic Cancer in Patients With Undifferentiated Pruritus
Authors: Junwen Deng, Varsha Parthasarathy, Waleed Adawi, Zachary Bordeaux, Nishadh Sutaria, Abhishek Gami, Matthew Taylor, Kevin K. Lee, Melika Marani, Isabelle Brown, Anusha Kambala, Hannah L. Cornman, Ali Alajmi, Thomas Pritchard, Olusola O. Oladipo, Yevgeniy R. Semenov, Shawn G. Kwatra
Journal: JAMA Dermatology (2022)

Although pruritus is common in patients with hematologic cancers, it is unknown whether patients with undifferentiated pruritus have higher risk of developing hematologic cancer. Furthermore, it is unclear whether serum lactate dehydrogenase (LDH) level, commonly ordered for cancer workup, has diagnostic utility in patients with pruritus.To assess the risk of hematologic cancer and the diagnostic utility of LDH level in patients with undifferentiated pruritus.This retrospective population-level cohort analysis was conducted using the TriNetX Research Network, a global health records database encompassing more than 69 million patients, from 2002 to 2020. The study included 327 502 eligible patients diagnosed with unspecified pruritus, excluding those with existing chronic pruritic dermatoses or systemic diseases known to cause pruritus, along with 327 502 matched controls.Development of hematologic cancer within 1 year, 5 years, and 10 years following unspecified pruritus diagnosis.Primary study outcomes were 1-year, 5-year, and 10-year relative risks (RRs) for development of 9 hematologic cancers in patients with pruritus compared with control patients. Secondary outcomes were 1-year, 5-year, and 10-year RRs for any hematologic cancer at different LDH cutoffs (250 U/L and 500 U/L).After matching, the pruritus and control cohorts each had 327 502 patients (68.1% female patients; 0.4% American Indian or Alaska Native patients; 3.5% Asian patients; 22.2% Black patients; 0.1% Native Hawaiian or Pacific Islander patients; 59.3% White patients; mean [SD] age, 42.2 [22] years). Patients with pruritus had increased 1-year risk of Hodgkin lymphoma (RR, 4.42; 95% CI, 2.83-6.88), myeloid leukemia (RR, 2.56; 95% CI, 1.79-3.67), multiple myeloma (RR, 2.38; 95% CI, 1.66-3.41), non-Hodgkin lymphoma (RR, 2.35; 95% CI, 1.96-2.82), monoclonal gammopathy (RR, 1.90; 95% CI, 1.55-2.32), myelodysplastic syndrome (RR, 1.74; 95% CI, 1.14-2.64), and lymphocytic leukemia (RR, 1.47; 95% CI, 1.07-2.02). After 12 months, the cancer risk was comparable with that of controls. Patients with pruritus had increased LDH levels, which were not associated with increased hematologic cancer risk.In this cohort study, the RR of hematologic cancer in patients with undifferentiated pruritus was highest in the first 12 months, and LDH level had limited diagnostic utility in these patients. Clinicians should consider a thorough review of symptoms and assessment of cancer risk factors when deciding on workup for patients presenting with undifferentiated pruritus.